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H3K9 dimethylation safeguards cancer cells against activation of the Interferon pathway [WGBS]

ABSTRACT: Activation of interferon genes constitutes an important anticancer pathway able to restrict proliferation of cancer cells. Here we demonstrate that the H3K9me3 histone methyl transferase (HMT) Suppressor of Variegation 3-9 Homolog 1 (SUV39H1) is required for the proliferation of Acute Myeloid Leukemia (AML) and find that its loss leads to activation of the interferon pathway. Mechanistically, we show that this occurs via destabilization of a complex composed of SUV39H1 and the two H3K9me2 HMTs, G9A and GLP. Indeed, loss of H3K9me2 correlated with the activation of key interferon pathway genes, and interference with the activities of G9A/GLP largely phenocopied loss of SUV39H1. Finally, we demonstrate that inhibition of G9A/GLP synergized with DNA demethylating agents and that SUV39H1 constitutes a potential biomarker for the response to hypomethylation treatment. Collectively, we uncovered a clinically relevant role for H3K9me2 in safeguarding cancer cells against activation of the interferon pathway.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182056 | GEO | 2022/03/18

REPOSITORIES: GEO

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H3K9 dimethylation safeguards cancer cells against activation of the Interferon pathway [SUV39H1_ChIP-seq]

Project description:Activation of the interferon genes constitutes an important anticancer pathway, able to restrict proliferation of cancer cells. Here we demonstrate that the H3K9me3 histone methyl transferase (HMT) Suppressor Of Variegation 3-9 Homolog 1 (SUV39H1) is required for the proliferation of Acute Myeloid Leukemia (AML) and find that its loss leads to activation of the interferon pathway. Mechanistically, we show that this occur via destabilization of a complex composed of SUV39H1 and the two H3K9me2 HMTs G9a and GLP. Indeed, loss of H3K9me2 correlated with the activation of key interferon pathway genes and interference with the activities of G9a/GLP largely phenocopied loss of SUV39H1. Finally, we demonstrated that inhibition of G9a/GLP synergized with DNA demethylating agents and that SUV39H1 constitutes a potential biomarker the response to hypomethylation treatment. Collectively, we uncovered a clinical relevant role for H3K9me2 in safeguarding cancer cells against activation of the interferon pathway.

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Project description:GLP (EHMT1) functions as an H3K9me1 and H3K9me2 methyltransferase through its reportedly obligatory dimerization with G9A (EHMT2). Here, we investigated the role of GLP in oocyte and embryo development in comparison to G9A using oocyte-specific conditional knockout mouse models (G9a cKO, Glp cKO, G9a-Glp cDKO). Loss of GLP in oogenesis severely impairs oocyte maturation, fertilization and embryo development, resulting in lethality before embryonic day E12.5. In contrast, loss of G9A has a milder effect with a proportion of embryos producing viable offspring. The Glp cKO also showed loss of G9A protein and, hence, was phenotypically very similar to the G9a-Glp cDKO. H3K9me2 was equally depleted in all cKO genotypes, whereas H3K9me1 was decreased only in Glp cKO and G9a-Glp cDKO oocytes. Furthermore, the transcriptome, DNA methylome and proteome were markedly more affected in G9a-Glp cDKO than G9a cKO oocytes, demonstrating that in the absence of GLP there are widespread epigenetic and gene expression changes in the oocyte independent of H3K9me2. Gene dysregulation with coupled changes in DNA methylation suggest localised loss of chromatin repression, resulting in upregulated protein expression. Together, our findings demonstrate that GLP can function independently of G9A in the oocyte and is required for oocyte developmental competence.

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Identification of proteins stably associated with G9a/GLP (EHMT2/EHMT1) complex of histone methyltransferases

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